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Microscopy & Imaging by Heather Hobbs


Crowdsourcing powers early discovery for SARS-CoV-2


soaked crystals were screened within weeks to identify 78 hits that densely populated the enzyme’s active site.


By making all data immediately available, with all compounds purchasable from the Ukrainian chemistry supplier Enamine, the consortium aims to accelerate research globally along parallel tracks following up on their initial work. “The data set enclosed in the Science publication provides a unique resource linking comprehensive structural data, fragment hits, multiple chemical scaffolds, as well as biochemical and cellular assay data that can be viewed and exploited by other scientists” said Dr Lizbe Koekemoer, a lead author and team leader at the Centre for Medicines Discovery, University of Oxford.


Covid Moonshot Collaborators – left to right: Benjamin Perry, Discovery Open Innovation Leader at DNDi; Frank von Delft, Professor of Structural Chemical Biology at the University of Oxford and Principal Beamline Scientist at Diamond Light Source; John Chodera, Associate Member at the Memorial Sloan Kettering Cancer Center and founding member of the Folding@home Consortium; Annette von Delft, Translational Scientist at the University of Oxford ; Ed Griffen, Technical Director and co-founder of MedChemica; Alpha Lee, Chief Scientifi c Offi cer at PostEra and Faculty Member at the University of Cambridge. (Credit: Diamond Light Source)


Celebrating World Science day during November, a study by the COVID Moonshot Consortium has emphasised the success of its use of crowd sourcing and Open Science to accelerate its discovery of both a potent SARS-CoV-2 antiviral lead compound and the launch of a patent-free antiviral discovery program for rapid lead development in response to a pandemic emergency.


The UK’s National Synchrotron, Diamond Light Source, played a pivotal role in the success of the consortium’s research. Many of the discoveries enabled by Diamond have been crucial to some of the most defi ning science in recent history – from kickstarting Covid treatments and deconvoluting the effi cacy of the Covid vaccine, to advancing treatment for many diseases from HIV, Foot and Mouth Disease to Cancer, and even identifying a plastic eating enzyme that may help solve the plastic pollution of our planet.


Triggered by a Twitter appeal, COVID Moonshot started as a spontaneous virtual initiative in March 2020, attracting more than 200 scientists and students from academia and biopharma to join forces in an unprecedented, fully open collaboration, which rapidly identifi ed and developed novel compounds with excellent antiviral activity against a key enzyme of the SARS-COV-2 virus, namely the main protease (Mpro).The lead candidate is now in pre-clinical evaluation in collaboration with Drugs for Neglected Disease Initiative (DNDi). The COVID Moonshot is dedicated to the discovery of safe, globally affordable antiviral drugs against COVID-19 and future viral pandemics, and is pioneering a straight-to-generic, patent-free approach.


The consortium’s paper [1] reports on the discovery of a non- covalent, non-peptidic inhibitor scaffold with lead-like properties that is differentiated from current main protease inhibitors. Their approach leveraged crowdsourcing, machine learning, exascale molecular simulations and high-throughput structural biology and chemistry. It built on data from a large experiment, performed in record time at the start of the pandemic, at Diamond’s XChem facility for crystallographic fragment screening using Diamond’s high-throughput crystallography. In the experiment, 1,495 fragment-


“This is the fi rst time such a large number of protein-ligand structures have been generated for a drug discovery campaign and released in the public domain. It is a testament to Diamond’s high- throughput crystallography infrastructure, but also the astonishing coordination across many research groups worldwide under enormous pressure” added Dr Daren Fearon, another lead author and Senior Beamline Scientist at Diamond Light Source, who leads the XChem facility.


Dr Annette von Delft, University of Oxford said; “This publication showcases the enormous value that crowd-sourcing can bring to drug discovery. The COVID Moonshot project has been unique in its collaborative approach and commitment to open science and


Aerial view of Diamond Light Source (Credit: DLS)


research using our facility. Bringing together experts in physical and life science innovations, cross disciplinary teams, and access to collaborative facilities allows our users to shine their brilliance on new technologies, treatments, sustainable materials and climate solutions for the many 21st century challenges we face,” commented Diamond’s CEO, Gianluigi Botton.


Gianluigi Botton CEO Diamond (Credit: DLS) demonstrates how collaboration can be a driver for innovation.”


As a striking example for the impact of open-science, the Shionogi clinical candidate S-217622, which is available in Japan under emergency approval as Xocova [ensitrelvir], was identifi ed using the data generated at Diamond and openly released. Senior author Professor Frank von Delft, Principal Beamline Scientist at Diamond, Professor for Structural Chemical Biology at University of Oxford and one of the founders of the consortium, commented, “Open science efforts have transformed many areas of biosciences. The COVID Moonshot provides an exemplar of a viable route to open science early drug discovery leading to advances in infectious diseases drug discovery—a research area of grave public importance but one which is chronically underfunded by the private sector. The Moonshot structure-enabled drug discovery campaign targeting the coronavirus main protease is providing a roadmap for the potential development of future antivirals.”


“Every day at Diamond, we are proud to be working with leading scientists and academics from all over the world like the COVID Moonshot Consortium, who are conducting innovative and inspired


Frank von Delft, Principle Beamline Scientist 104l (Credit: Diamond Light Source)


The discovery platform collaboration that spontaneously formed as the COVID Moonshot now continues its work as the ASAP discovery consortium, (AI-driven Structure-enabled Antiviral Platform), aiming to discover and develop novel broad-spectrum small molecule inhibitors against coronaviruses, fl aviviruses and enteroviruses for pandemic preparedness.


The initiative is a collaborative effort of the Nuffi eld Department of Medicine at the University of Oxford; Diamond Light Source; PostEra; Weizmann Institute of Science; MedChemica Ltd; Icahn School of Medicine at Mount Sinai; Enamine Ltd; Memorial Sloan Kettering Cancer Center; and Thames Pharma Partners LCC.


[1] Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors ) DOI 10.1126/science.abo7201.


More information online: ilmt.co/PL/oByo 61748pr@reply-direct.com


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